Role of Cynlin-Dependent Kinases Inhibitors in Cell Growth Regulation and Cancer Thanh-Binh Nancy Le
Overview First: Introduce the Biological Review Second: Review the Drug Design Third: Demonstrate the Experiment
What is Cyclin-Dependent Kinases? • Cyclin-dependent kinases (CDKs) are a family of serine-threonine protein kinases.
what is the molecular structure of p21? • Six β -strands • Five α-helices
what is the function of p21 in cell cycle regulation? • Control and consequent loss of cell cycle checkpoints. • Stop cell cycle to induce differentiation and senescence.
What will happen if p21 is mutated? • Oncogenic mutation. • Higher barrier for conformational change. • Not undergo conformational change. • Rearrange Loop 4 • Increase the lifetime of the active state. • Results in continuation of signal for cell growth.
2-Anilino-4-(thiazol-5-yl) pyrimidine(1pxn). Ki = 0.07uM Length =298
How does 1PXN binds to the protein? • 1PXN bind to CDK2 at four ligands active site:
hydroxyfasudil (2ERZ) Ki=2.2uM Length=351
1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE (1YDR) Ki=3uM Length=350
balanol analog 1 (1REJ) Ki=5nM Ki=3nM Length =350
STAUROSPORINE (1STC) Ki=8nM Length=350
NU2058 (1H1P) Ki=12uM Length=303
Purpose of the Lab Understand Competitive binding of the Cyclin-Kinase Inhibitors CDK2 over the substrate. How different functional groups in the inhibitors play the inhibitor binding.
Method • Get CDK2 protein from pdb bank. • Creatingprmtop files • Create t-leap • Calculate the relative binding affinities of CDK inhibitors. • Using MM-PBSA in the Amber software
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